Fluoxetine prevents Aβ1-42-induced toxicity via a paracrine signaling mediated by transforming-growth-factor-β1

Selective reuptake inhibitors (SSRIs), such as fluoxetine and sertraline, increase circulating Transforming-Growth-Factor-beta 1 (TGF-beta 1) levels in depressed patients, and are currently studied for their neuroprotective properties in Alzheimer's disease. TGF-beta 1 is an anti-inflammatory cytokine that exerts neuroprotective effects against beta-amyloid (A beta)-induced neurodegeneration. In the present work, the SSRI, fluoxetine, was tested for the ability to protect cortical neurons against 1 mu M oligomeric A beta(1-42)-induced toxicity. At therapeutic concentrations (100 nM-1 mu M ), fluoxetine significantly prevented A beta-induced toxicity in mixed glia-neuronal cultures, but not in pure neuronal cultures. Though to a lesser extent, also sertraline was neuroprotective in mixed cultures, whereas serotonin (10 nM-10 mu M) did not mimick fluoxetine effects. Glia-conditioned medium collected from astrocytes challenged with fluoxetine protected pure cortical neurons against A beta toxicity. The effect was lost in the presence of a neutralizing antibody against TGF-beta 1 in the conditioned medium, or when the specific inhibitor of type-1 TGF-beta 1 receptor, SB431542, was added to pure neuronal cultures. Accordingly, a 24 h treatment of cortical astrocytes with fluoxetine promoted the release of active TGF beta 1 in the culture media through the conversion of latent TGF-beta 1 to mature TGF-beta 1. Unlike fluoxetine, both serotonin and sertraline did not stimulate the astrocyte release of active TGF-beta 1. We conclude that fluoxetine is neuroprotective against 4 toxicity via a paracrine signaling mediated by TGF-beta 1, which does not result from a simplistic SERT blockade.